Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

Ann. rheum. Dis. (1963), 22, 127.

ORIGIN OF THE ASCHOFF BODY

BY BERNICE G. WEDUM Study, Frederick, Maryland AND JOHN W. McGUIRE Photography Section, Medical Arts and Photography Branch, Division of Research Services, National Institutes of Health, Bethesda, Md. Rheumatic fever has been compared with tuber- students of rheumatic fever for the next 150 years. culosis (Thorel, 1910; Fahr, 1930), Hodgkin's Ludwig Aschoff directed his attention to this disease (Aschoff and Tawara, 1906; Gross, Loewe, problem in his first paper (1904), seeking for evidence and Eliasoph, 1929), and hypersensitivity reactions that the conduction system of the was affected (Swift, 1924; Klinge, 1933). The ultimate, com- in acute rheumatism and was responsible for the plete explanation of its pathogenesis must explain functional disorder, an idea previously advanced by why it has presented such varying aspects to such Peter (1891). Aschoff found no evidence to support profound students of the disease. The present study such a theory in the three cases which were the concerns the nature of its most specific pathological subject of his first paper, but Aschoff and Tawara

manifestations, the Aschoff body of the heart. (1906), in their monograph on the failing heart, copyright. Evidence is presented that the Aschoff body is described one case with considerable involvement of derived from the larger lymphatic vessels of the the bundle of Hiss. They came to the conclusion heart; the central core, which may be present, is that the basic disorder was an anaemic of composed of precipitated lymph and necrotic the myocardium caused by perivasculitis of the protoplasm. These granulomata form at points of blood vessels supplying the muscle. They had mechanical stress, especially under the endo- found in the adventitia of the blood vessels "peculiar cardium and in the region of the intramyocardial nodules which were specific for rheumatic http://ard.bmj.com/ coronary . Damage to and ... developed by an aggregation of conspicuously is secondary to the lymphoedema large elements with one or more abnormally large, which follows obstruction of the lymphatic vessels slightly indented or polymorphous nuclei. The by the proliferating endothelial cells. It is most aggregation of these cells often takes the form of prominent at points of mechanical trauma, notably a fan or rosette. The periphery is formed by the at the point of closure of the heart valves, where large nuclei, and the centre by apparently necrotic form. protoplasm, staining here weaker and somewhat vegetations on September 28, 2021 by guest. Protected The existence of a rheumatism of the heart was different" (Aschoff, 1904). first clearly defined by Dundas (1809), although The greatness of Aschoff's contribution lies not Jenner (1789) had written an account of the associa- only in his recognition of a specific for tion (his manuscript was subsequently lost), and it rheumatic carditis, but also in his recognition that had also been mentioned by Pitcairn (1797) and the damage to the myocardium was in some manner Odier (1806). In his second edition, Odier (1811) secondary to the specific lesion in the connective reported two cases of rheumatic adhesive peri- tissue. Poynton (1899) had also appreciated that carditis in a footnote, and concluded, "But what is "the function of cardiac muscle is damaged in a difficult to understand is that this complete adher- peculiar way, rather than destroyed by the rheumatic ence of the two organs which are naturally detached poison". (The term "peculiar disease of the heart" one from the other did not in any way disturb the had been used by Dundas (1809), Aschoff wrote of circulation." "peculiar nodules", and years later MacCallum Thus at the beginning of the 19th century the (1924) was to mention "lymphatic channels filled question was asked why the heart failed in rheu- with lymphocytes which form a peculiar and rather matic carditis, and this question was to occupy conspicuous feature", and that rheumatic fever was 127 Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

128 ANNALS OF THE RHEUMATIC DISEASES caused by a specific infectious agent of some concerned with the pathology of rheumatic heart peculiar kind (MacCallum, 1925). In identical disease, assuming that the Aschoff cell was derived language these able students of the disease expressed from some type of connective tissue cell. Interest their awareness of something unusual and not centred chiefly in the mode of formation of this cell, heretofore encountered in rheumatic carditis.) whether by mitotic or amitotic division of nuclei, With only a few dissenting voices, the specificity which would suggest a mechanism of pathogenesis of the granuloma described by Aschofffor rheumatic involving DNA, or by fusion, which would suggest carditis was widely accepted. The exact origin of an alteration in the cell membrane. Studies on the the characteristic remained in doubt. aetiology of rheumatic fever in progress in our The majority considered it to be some type of con- laboratory included the use of tissue culture of left nective tissue or endothelial cell (Aschoff, 1904, auricular appendages obtained at surgery for mitral 1906; Geipel, 1905; Fraenkel, 1912; Swift, 1924; stenosis. With the appearance of the monograph Letulle, Bezanqon, and Weil, 1926; Clawson, Bell, by Murphy (1960), suggesting the origin of the and Hartzell, 1926). A few (Huzella, 1914; Whit- Aschoff cell from the myofibre itself, it seemed man and Eastlake, 1920; Murphy, 1960) considered essential to re-investigate this question in order to be this giant cell to be derived from the myocardial certain that our experimental approach was sound. fibre itself. Others, while holding to the view that Connective tissue cells migrate in tissue culture, but the Aschoff cell was a connective tissue cell, believed the myofibre does not. that giant cells could also arise from the myocardium (Saigo, 1908; Letulle, Bezanqon, and Weil, 1926; Wagner and Tedeschi, 1955). The views of many Present Investigations investigators have been summarized by McEwen It seemed that the pathology of rheumatic (1932). carditis would be seen most clearly in patients dying The important question debated during the next in the course of a first attack of rheumatic fever. 25 years was whether the central core of the An effort was made, therefore, to obtain material granuloma described so carefully by Aschoff as from as many early cases as possible. Such cases copyright. "necrotic protoplasm" was in fact the primary are rare, but it was possible to collect six with three lesion. Klinge (1933), in his monumental study of additional cases of children of similar age dying of all forms of rheumatism, concluded that exudation causes unrelated to the heart to serve as controls was the primary process, consisting of a specific (Table, overleaf, p. 129). Details are given in the type of damage to fibrils. He also stated, Appendix, p. 139. however, that proliferation and exudation might Method occur simultaneously and, in agreement with http://ard.bmj.com/ Talalajew (1929), that perhaps in the heart the The co-author (J.W.McG.) pointed out that primary process was cellular proliferation. Aschoff details could be seen on large colour transparencies (1939) published pictures showing undamaged which were not apparent under the microscope. fibrils in early Aschoff bodies and maintained that A series of eighty 8 x 10-inch colour transparencies, rheumatic carditis was essentially a proliferative some at magnifications as high as 2,450, was taken disease of cells. Rheumatic fever, nevertheless, of the sections, exploring each system of the heart. became known as a collagen disease and the search It was then to the transparencies, possible examine on September 28, 2021 by guest. Protected for the aetiologic agent became an inquiry into the using a view box, and to study them over long mechanism by which this alteration in collagen was periods, sometimes with the aid of a hand lens. produced. Still unanswered was the question how myocardial function was so profoundly altered as a result of connective tissue damage. Results For more extensive reviews the writings of Itard In the course of these studies a dilated lymphatic (1824), Eulenberg (1854), Besnier (1877), Janot vessel, its endothelial lining cells exhibiting unusual (1902), Gallavardin (1908), Jacki (1919-20), Bezan- features in that they resembled early Aschoff cells, (on and Well (1926), Sacks (1926), Paul (1928), was noted between two blood vessels (Figs 1 and 2, Clawson (1929), Klinge (1933), Gross and Ehrlich opposite). A search for lymphatic vessels in (1934), Wilson (1940), Baggenstoss (1953), Murphy sections of normal revealed none which could (1943, 1960) should be consulted, together with the be discerned, nor were there any special stains section on rheumatic fever in the Rheumatism and available to differentiate lymphatic vessels from Arthritis Review (1962). surrounding connective tissue. For the past 20 years the writer (B.G.W.) has been IAn inquiry into the anatomy of the lymphatic Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

ORIGIN OF THE ASCHOFF BODY

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Fig. 10.-Aschoff body forming from lymphatic channel cut in cross- Fig. 12.-Aschoff body forming from lymphatic channels cut in longi- section with roseate structure. Case 4. x 175. tudinal section with parallel "ribbons" of cells. Case 4. x 175.

[facing page 128 Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

ORIGIN OF THE ASCHOFF BODY 129

TABLE PARTICULARS OF SIX PATIENTS AND THREE CONTROLS

Case Sex (yrs) Race Hospital Physician History Diagnosis Rheumatic Cases 1 -_ -_ Armed Forces Institute of Dr. W. Manion _ Acute rheumatic carditis Pathology, Washington, D.C. 2 F 6j Col. Children's Hospital, Dr. P. Vanace Dr. S. Friedman Rheumatic pancarditis Philadelphia, Pa. 3 F 4 Col. Armed Forces Institute of Dr. W. Manion Deartment of Path- Rheumatic pancarditis Pathology, ology, Louisiana Washington, D.C. State University, School of , Dr. H. C. McGill 4 M 10 Wh. Armed Forces Institute of Dr. W. Manion New York University Acute rheumatic myo- Pathology, Medical Centre, carditis Washington, D.C. Dr. N. Cooper Rheumatic pneumonitis 5 M 5 Col. Children's Hospital, Dr. P. Vera Cruz Dr. H. Wigger Acute rheumatic carditis Washington, D.C. 6 M 3 Ind. Belcourt Indian Hospital, Dr. G. Laqueur Dr. G. Laqueur Rheumatic pancarditis N. Dakota with rheumatic pneu- monia; cardiac massage

Non-Rheumatic Control Cases 1I M 4 Wh. Brackenridge Hospital, Dr. E. Gilbert Dr. E. Gilbert Broncho-pneumonia; I Austin, Texas Cardiac arrest; Cardiac massage

2 F 5 Wh. Congenital Heart Disease Dr. M. Lev Dr. M. Lev Wilm's tumour right copyright. Research and Training kidney Centre, Chicago, Ill. Mount Sinai Hospital, New York 3 F 6 Wh. Johns Hopkins Hospital, Dr. J. Frost Dr. J. Frost Cerebellar astrocytoma Baltimore, Md.

Case 1: Figs 1-4, 24-26. Case 2: Figs 14, 15, 17, 22, 23. http://ard.bmj.com/ Case 3: Figs 20, 21 Case 4: Figs 5-13, 16. Case 6: Figs 18, 19. vessels of the heart led us to the writings of Patek the venules to the interstitial connective tissue septa. (1939) and Roberts (1959). According to the The epicardial plexus is loosely arranged in the latter, the lymphatic vessels of the heart consist of subepicardial connective tissue. All the lymphatic on September 28, 2021 by guest. Protected four subdivisions: the subendocardial plexus, the drainage channels usually unite in a single trunk myocardial plexus, the epicardial plexus, and the which joins a left mediastinal plexus of lymphatic lymphatic drainage channels. The subendocardial vessels. plexus is made up of small lymphatic channels Re-examination of the sections from the available forming a branching and anastomotic network with cases indicated that the topography of the distribu- large meshes lying in the subendocardial connective tion of Aschoff bodies closely followed that of the tissues of all four chambers of the heart. The lymphatic channels described by Roberts (1959). myocardial plexus comprises a more voluminous Closer study suggested that the Aschoff body itself system of lymphatic capillaries and small channels, might be a diseased lymphatic channel, ultimately which form a network very closely similar to the converted into a solid granuloma, sometimes with blood vascular plexus of capillaries and vessels a central core of precipitated lymph and necrotic throughout the myocardium. The lymphatic capil- protoplasm. In Figs 3 to 26 an attempt is made to laries lie close to the blood capillaries in the inter- illustrate the sequence of events leading from early stitial spaces between adjacent muscle fibres and endothelial changes within the lymphatic vessels drain into larger lymphatic channels, which follow to the Aschoff body. 2 Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

130 ANNALS OF THE RHEUMATIC DISEASES

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Fig. 3.-Distended lymphatic channels near small vessel. Case 1. x 175. Fig. 4.-Lymphatic vessels in Fig. 3, showing swelling of nuclei of endothelium. One multinucleated cell is present. Case 1. x 1,040. http://ard.bmj.com/ Initially the nuclei of the delicate, flat endothelial cells lining the lymphatic channels increase in volume (Figs 3 and 4); the primary event appears to be this change in the nucleus. Central condensa- tion of the chromatin ensues with simultaneous swelling of the entire cell, the cytoplasm becoming .A.I.i.--s 4.11, -V... and uniformly granular and strongly eosino- on September 28, 2021 by guest. Protected finely ASOL philic. Very early, more than one nucleus is seen in the endothelial cell; this would appear .44m: dob-- to be a result of nuclear division, although in a careful search for mitotic figures in Aschoff cells only one was found (Fig. 5). (The original slide was examined by Dr. Yu Hin Tjio, who confirmed this observation.) *i ow. -F Atw - .,..:9,t.:r X

x;-i. Size. B;: The lymphatic channel remains recognizable as _ a. .''' .w_ .... such for a short period only (Fig. 6, opposite). The .4# lumen of the vessel becomes progressively replaced by accumulated cytoplasmic debris and protein- aceous material (Figs 7 and 8, opposite). A central core may thus result, consisting of granular eosino- Ant'+ t¢*tt philic amorphous material (Fig. 9, opposite). Fig. 5.-Mitotic figure in Aschoff cell. Case 4. x 1,040 Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

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Fig. 8.-Lymphatic channel forming early Aschoff body. Note Fig. 9.-Aschoff body forming from lymphatic vessel, showing core distended lymphatic capillaries. Case 4. x 175. of precipitated lymph and cell protoplasm. Case 4. x 175. Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

132 ANNALS OF THE RHEUMATIC DISEASES

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In cross-section the early Aschoff body resembles a roseate structure (Fig. 10 (col. pl.), and Fig. 11), while in longitudinal section the effect is that of / I /~B parallel "ribbons" of cells (Fig. 12 (col. pl.), and Fig. 13). The derivation of this granuloma from http://ard.bmj.com/ a lymphatic channel gradually becomes more difficult to discern (Figs 14 and 15) as the swollen /.. ~~... 4.v VP on September 28, 2021 by guest. Protected :., ,,... : He~~~~~W4.*. * '9 4 U.*S,.# ~~~. .. *

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ORIGIN OF THE ASCHOFF BODY 133 cells with their proliferating nuclei are desquamated to the heart. into the lumen; ultimately a solid mass of cells The nucleus of the myofibre may be seen to be results (Fig. 16). swollen, with the chromatin re-arrangement typical The endocardium is swollen two or three times of the true Anitschkow myocyte. The cross stria- its normal thickness. In the subendocardial lymph- tions may be lost and the parenchyma gradually atic plexus, channels may be identified as such only disappear, leaving in the path of the muscle track occasionally; indirect evidence that they are involved the more durable nuclei. These may be present in is provided, however, by the distended lymphatic apparently larger numbers than would be accounted capillaries which radiate out on either side of the for by the muscle track, suggesting an attempt at bands of flattened Aschoff bodies which appear division and regeneration. Occasionally there are to be derived from this plexus (Fig. 17). These clumps of degenerating muscle cells which closely capillaries contain lymphocytes, polymorphonuclear resemble the true Aschoff cell (Fig. 20, overleaf). leucocytes, and larger cells with eosinophilic cyto- These changes in the muscle are found most often in plasm, which are occasionally multinucleated. the immediate vicinity of Aschoff bodies. The myo- The is markedly oedematous and fibrils in other areas show no changes when com- two or three times its normal thickness. Distended pared with the control cases, with the exception of lymphatic channels may be seen particularly well in Cases 1 and 6. In Case 1 changes are found Case 6 (Figs 18 and 19, overleaf). The endothelial throughout the section-a fine granulation of the cells show the same swelling of nucleus and cyto- sarcoplasm, unevenness of staining properties, and plasm and occasionally have two or three nuclei. separation of the muscle fibres, apparently by Large multinucleated Aschoff cells are not often oedema. A number of the nuclei of the myofibrils seen, and only two Aschoff bodies were identified, in Case 6 have the characteristics of the true both in the adventitia of the coronary sinus in Anitschkow myocyte. Cases 1 and 6. The coronary arteries show separation of the The lymphoedema resulting from the blockade adventitial fibres which is apparently due to oedema. of the lymphatic vessels by the proliferating endo- Where larger Aschoff bodies lie adjacent to them, the thelial cells appears to result in further damage copyright.

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134 ANNALS OF THE RHEUMATIC DISEASES

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ORIGIN OF THE ASCHOFF BODY 135 endothelium of the intima occasionally shows slight Fig. 24 (overleaf) shows the principal types of swelling, and in Case 3 separation of the con- damage in early rheumatic carditis. stituents of the media is sometimes noted. For the most part, however, the blood vessels show little An Aschoff body is forming from a lymphatic change even in the vicinity of Aschoff cells (Fig. 21, channel (Fig. 25, overleaf). opposite). Although the capillaries are engorged with blood, the capillary endothelium is normal. The connective tissue between two vessels which seem to be arterioles appears to have been com- In the connective tissue an increase in the number pressed between the two vessels; the ground sub- of fibroblasts is sometimes seen, especially in the stance is amorphous and there is lymphocytic region of Aschoff bodies. At points of mechanical and eosinophilic infiltration (Fig. 26, overleaf). trauma, damage to the oedematous connective Muscle tracks in the immediate vicinity show loss of tissue may occur; the delicate fibrils become indis- parenchyma with persistence of nuclei. tinct and eosinophilic, with lymphocytes and eosino- phils between them. The mitral valve in Case 2 is The limited amount of material presented, all swollen to two or three times its normal thickness, stained with haematoxylin and eosin, did not permit when compared with the control cases. Several us to draw definite conclusions concerning the distinct lymphatic vessels are present just below the conduction system. It lies close to the subendo- endocardium (Fig. 22) and at the point of closure cardial lymphatic plexus, however, and changes in a small vegetation is seen (Fig. 23). A moderate its function are manifested early in rheumatic number of Aschoff cells appear in the aortic valve carditis by changes in the PR-interval of the electro- in Case 5. cardiogram. copyright.

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Discussion reaction, with widespread involvement of the capil- lary endothelium. The reaction is limited to sites Watson (1835) stated that "The heart is spoiled in the area of well-developed Aschoff bodies and to for its healthy and perfect use by the lymph deposit areas where the pressures are very high-in the within it and without it. If it were possible to vicinity of some of the intramyocardial coronary prevent this destructive effect of the , arteries and at the point of closure of the mitral on September 28, 2021 by guest. Protected that should be our goal, but we can scarcely ever valve. Here the impact of the oedematous cusps expect to recognize and treat. the disease before a against one another causes a "blister" of vegetation diffusion of lymph has taken place." A little more to form (Swift, 1924). No vegetations were seen than 100 years later Primak (1940) observed dilated on the valves at autopsy in Cases 3 and 6. lymph vessels and lymph congestion in the myo- Death from rheumatic carditis must result from cardium of patients who died of carditis. Rusznyack, myocardial failure. All students of this subject Foldi, and Szabo (1960) appear to have been the have been faced with the dilemma posed by this first to ask whether an obstructive lymphangitis uncontestable fact and the normal appearance of might be the cause of these findings. cardiac muscle fibres on microscopic examination. The damage to connective tissue, ground sub- In this series only Cases 1 and 6 gave a hint of stance, and muscle cells is limited to certain areas generalized damage to the myocardium. In the in these early cases. These systems are remarkably other cases, except in the region of Aschoff bodies, normal in most areas of the heart. If a toxic the appearance of the cardiac muscle is, if anything, substance escaping from the capillaries were causing better than that in the sections from non-rheumatic damage, one would expect to find a more generalized hearts of the same age. Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

ORIGIN OF THE ASCHOFF BODY 137

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hand, are present throughout the heart in all these must occur long before damage which can be recog- http://ard.bmj.com/ cases. The contrast between the normal myo- nized by relatively crude histological procedures. cardium and extensive involvement of the lymphatics is especially striking in Case 3, where there appears The sites of occurrence of Aschoff bodies are in to have been a previous attack. Many of the part conditioned by mechanical pressure. Those lymphatic vessels are obliterated-those under the sites where the pressure is high, under the endo- endocardium, those in the pericardium, and those cardium and in the vicinity of the intramnyocardial coursing in the myocardium close to the blood coronary arteries (where pressures are high in vessels, leaving partial cuffs of scar tissue around the diastole as well as in systole), are relatively frequent on September 28, 2021 by guest. Protected latter. As is well known, one attack of carditis sites of granulomata. These lesions are less com- predisposes to future attacks. Although lymphatic monly found in the pericardium, which acts as a vessels quickly recanalize after ligation, progressive loose envelope during systole; in this area the fibrosis of the system would cause subsequent diseased lymphatic endothelial cells do not so often episodes of acute inflammation to obstruct the form giant cells. It is also the larger lymphatic lymphatic drainage of the heart more and more channels which show the most pronounced involve- readily. ment; this suggests that the rheumatic agent may, in fact, reach the heart in a retrograde fashion The impairment of myocardial function is not in these early cases through the lymphatics of the only mechanical because of the oedema, but neck and thorax. There is a possibility that the functional because of disturbances in metabolism lymph in the intracellular spaces becomes in some caused by the stasis which is caused in its turn by manner concentrated when it reaches the larger the lymphatic blockage. This is a situation which channels of the heart; a search of the literature has could perhaps be tolerated by an organ at rest, but revealed no positive evidence for or against such in the rapidly beating heart disorder of the com- a concept. Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

138 ANNALS OF THE RHEUMATIC DISEASES Cells with "caterpillar" or "owl-eyed" nuclei were Grateful acknowledgement is made to the following for seen in sections of non-rheumatic hearts from their contributions to this study: Dr. William Manion, children of the same age, and were especially notice- Dr. Peter Vanace, Dr. Maurice Lev, Dr. James Frost, cardiac massage Dr. Enid Gilbert, Dr. Gert Laqueur, Dr. Grace Guinn, able in the heart of a child on whom Dr. Hans Wigger, Dr. Louis Thomas, Dr. Hugh McGill, had been performed immediately before death. Dr. Chandler Stetson, Dr. Norman Cooper, Dr. Pia They may perhaps result when a cell in one of the Vera Cruz, Dr. Dorothy Bocher, Dr. Robert Pollitzer, phases of mitosis is subjected to great pressure. Dr. Irwin Fuhr, Mrs. Dora Lee Agayoff, Miss Elizabeth Eosinophils are conspicuously absent in early Moseley, Mr. William Macy, Mrs. Betty Henry, Mr. Aschoff bodies; they may, however, be present in Alvin Barnes, Miss Faye Haupt, and Mr. Frank J. great numbers in the most fulminating cases of car- Golden. ditis. They are also present in areas where secon- The National Library of Medicine, the Library of the dary damage to connective tissue of the heart has Clinical Centre National Institutes of Health, the occurred. In the earliest case (Case 1) they were Archibald Church Memorial Library, Northwestern found in any number in only two small areas. In one University Medical School, the John Crear Library, and area a small capillary was thrombosed; here there the British Museum Library gave invaluable assistance were a few scattered red blood cells lying free in the in the preparation of the bibliography. adjacent interstitial spaces, two degenerating muscle Especial appreciation is expressed to Dr. Gert Laqueur, cells, and a moderate infiltration of polymorpho- for encouragement and advice in the preparation of the nuclear leucocytes, about half of which, by count, pathological descriptions, and to Mrs. Nina Smith, who were eosinophils. The other area has been des- carefully read the manuscript and translated certain cribed (Fig. 26). There appears to be some product German publications. of tissue break-down in the heart which quickly This work was supported by research grant H3554 provokes an eosinophilic response. of the National Heart Institute of the National Institutes Many questions remain unanswered. One is the of Health. relation of the pathogenesis of the Aschoff body to the formation of the rheumatic subcutaneous REFERENCES copyright. nodule. The brain has no lymphatic vessels, Aschoff, L. (1904). Verh. dtsch. path. Ges., 8, 46. although perivascular collections of lymphocytes (1939). Ann. rheum. Dis., 1, 161. are found in its substance in chorea. Possibly it and Tawara, S. (1906). "Die heutige Lehre von is the lymphatic vessels of the meninges which are den pathologisch-anatomischen Grundlagen der affected. The question whether the joint mani- Herzchwache." Fischer, Jena. festations are also a result of an obstructive lymph- Baggenstoss, A. H. (1953). In "Pathology of the angitis, and the cause of the many so-called minor Heart", ed. S. E. Gould, p. 679. Thomas, http://ard.bmj.com/ manifestations of rheumatic fever (rashes, nose- Springfield, Ill. Besnier, E. (1877). "Rhumatisme Cardiaque." Dict. bleeds, abdominal pain) await further study. enclosed. Sci. mid., 3 ser., 4, 528. The concept of the pathogenesis of rheumatic Bezangon, F., and Weil, M.-P. (1926). Ann. mid. Paris, carditis which has been presented is a return to the 19, 81. original view of Aschoff, who regarded the primary Clawson, B. J. (1929). Arch. Path., 8, 664. damage in rheumatic carditis as a proliferation of Bell, E. T., and Hartzell, T. B. (1926). Amer. J. 193. cells in response to a rheumatic virus. The strepto- Path., 2, on September 28, 2021 by guest. Protected coccus appears to be the most common stressing Dundas, D. (1809). Med.-chir. Trans., 1, 37. factor in rheumatic fever in the temperate zone; Eulenberg, M. M. (1854). Med. Ztg. Berl., 23, 125, cause of the disease is as yet unknown. 129, 133, 139. the specific Fahr, T. (1930). Beitr. path. Anat., 85, 445. Fraenkel, E. (1912). Ibid., 52, 597. Gallavardin, L. (1908). Lyon mid., 110, 753. Summary Geipel, P. (1905). Dtsch. Arch. klin. Med., 85, 75. Gross, L., and Ehrlich, J. C. (1934). Amer. J. Path., (1) The pathology of six cases of fulminating 10, 467. rheumatic carditis has been studied, with three Loewe, L., and Eliasoph, B. (1929). J. Exp. Med., non-rheumatic hearts as controls. 50, 41. Evidence is presented that the Aschoff body Huzella, T. (1914). Verh. dtsch. path. Ges., 17, 470. (2) Itard, J.-I. (1824). These de Paris ["Considerations sur is a diseased lymphatic channel. le rhumatisme du coeur"]. (3) Damage to the myocardium and impairment Jacki, E. (1919-20). Frankfurt Z. Path., 22, 82. of its function are secondary to an obstructive Janot, A. (1902). These de Paris ["Contribution a lymphangitis. l'6tude de la myocardite rhumatismale aigue"]. Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

ORIGIN OF THE ASCHOFF BODY 139 Jenner, E. (1789). In W. R. LeFanu (1951). "A Bio- Poynton, F. J. (1899). Med.-chir. Trans., 82, 355. bibliography of Edward Jenner", p. 17. Harvey Primak, F. (1940). Starost, Kiev., p. 97. Quoted by and Blythe, London. Rusznyak and others (1960), p. 578. Klinge, F. (1933). Ergebn. allg. Path. path. Anat., Rheumatism and Arthritis Review (1962). Ann. intern. 27, 1. Med., 56 (5), Part 2. Letulle, M., Bezangon, F., and Weil, M.-P. (1926). Roberts, J. T. (1959). In "Cardiology: an Encyclopedia Ann. mid. Paris, 19, 117. of the Cardiovascular System", ed. A. A. Luisada, MacCallum, W. G. (1924). Bull. Johns Hopk. Hosp., vol. 1, p. 85. Blakiston Division, McGraw-Hill, 35, 329. New York, Toronto, London. (1925). J. Amer. med. Ass., 84, 1545. Rusznyak, I., Foldi, M., and Szabo, C. (1960). "Lymph- McEwen, C. (1932). J. exp. Med., 55, 745. atics and Lymph Circulation", trans. A. Deak Murphy, G. E. (1943). Bull. Hist. Med., 14, 123. and J. F6sus, p. 578. Pergamon Press, New York. (1960). "Nature of Rheumatic Heart Disease". Sacks, B. (1926). Amer. Heart J., 1, 750. Williams and Wilkins, Baltimore. Saigo, Y. (1908). Beitr. path. Anat., 44, 296. Odier, L. (1806). "Lezioni di medicina pratica". Trans. Swift, H. F. (1924). J. exp. Med., 39, 497. A. Dolcini, pp. 50, 194. Sonzogni, Bergamo. Talalajew, W. T. (1929). Klin. Wschr., 8, 124. (1811). "Manuel de medecine pratique", 2nd ed., Thorel, C. (1910). Ergebn. alug. Path. path. Anat., p. 254. Paschoud, Paris. abt. II, vol. 14, p. 133. Paul, J. R. (1928). Medicine (Baltimore), 7, 383. Wagner, B. M., and Tedeschi, C. G. (1955). Arch. Patek, P. R. (1939). Amer. J. Anat., 64, 203. Path., 60, 423. Peter (1891). Sem. mid. (Paris), 11, 93. Watson, T. (1835). Lond. med. Gaz., 16, 164. Pitcairn, D. (1797). Quoted by M. Baillie (1797). In Whitman, R. C., and Eastlake, A. C. (1920). Arch. "The Morbid Anatomy of Some of the Most intern. Med., 26, 601. Important Parts of the Human Body", 2nd ed., Wilson, M. G. (1940). "Rheumatic Fever". Common- p. 46. Johnson, London. wealth Fund, New York. copyright. APPENDIX Five Detailed Case Reports Case 2, a 6iyear-old coloured girl, was admitted to the right mid-zone. There were rhonchi at both bases, and Children's Hospital, Philadelphia, in 1958. questionable bronchial breathing at the mid-zone. Past History.-She had had measles, mumps, and The liver was enlarged 2 in. below the right costal http://ard.bmj.com/ whooping cough in 1955-56. margin and soft. There was shifting dullness on both flanks. The joints were painful and tender, with hot History of Present Illness.-She was well until 3 to swellings of fingers, wrist, and elbow on the right side. 4 weeks before admission, when she developed a cough Both ankles were swollen. The left knee and left hip and sore throat followed by intermittent fever unaffected were tender and painful. by oral penicillin. Her ankles swelled intermittently, but were not tender. The dorsa of the feet and the Clinical Impression.-Acute rheumatic carditis, in abdomen had become swollen 2 to 3 weeks before. failure, with questionable rheumatic pneumonia and 4 days before admission her eyes became puffy and on the lobar pneumonia. on September 28, 2021 by guest. Protected day of admission the right wrist became painful and Treatment.-Oxygen, aqueous penicillin, digitalin, swollen. aspirin, thiomerin, restricted fluid intake. She had had rapid breathing for 2 weeks, cough for Laboratory Tests.-Hb 6-6 g. per cent.; white blood 4 weeks, and blood-streaked sputum 2 days before count 29,800 (85 per cent. neutrophils, 14 per cent. admission. There was no haematuria, dysuria, or lymphocytes). Erythrocyte sedimentation rate 34 mm./ frequency of micturition. A skin-rash had been present 1st hr. on the abdomen for 3 days. Electrocardiogram showed changes indicative of Physical Examination.-Temperature 1010 F., myocarditis. 162/min., blood pressure 90/60. There was pallor, X rays showed enlarged cardiac shadow compatible bilateral pretibial oedema and oedema of dorsa of feet. with the enlarged heart of pericarditis, congestive changes AB was diffuse, no thrills. Muffled , in the lung fields, and possible pleural fluid accumula- I and II , loud low-pitched systolic murmur tions. maximal at the 5th left intercostal space. There was a Course in Hospital.-During the next 48 hours the questionable short diastolic murmur maximal at the patient improved, with subsidence offever, joint swellings, tricuspid area. There was flaring of the nostrils. The and tenderness, but she began to vomit and the aspirin percussion note was diminished at both bases and at the and digitalin were discontinued. She worsened markedly Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

140 ANNALS OF THE RHEUMATIC DISEASES for the next 24 hours with dyspnoea and a distressing Clinical Impression.-Acute rheumatic heart disease; cough. X rays of the chest revealed increasing lung congestive heart failure; broncho-pneumonia. involvement. On the fifth day she had two spells of Course.-The temperature varied from 100 to 102° F. apnoea and the blood pressure fell to 98/60. That and rose terminally to 1040. Despite all therapy he died evening her respirations increased to 80/min. She on the 13th day in hospital. suddenly complained of dizziness and became uncon- scious with frothy foam at the lips. Despite all resus- Final Diagnosis.-Acute rheumatic myocarditis; acute citative measures she died at 10 p.m. rheumatic valvulitis: tricuspid, mitral, and aortic valves; It should be noted that on the day before death the acute serofibrinous pericarditis; bilateral pneumonitis patient was started on intramuscular cortisone 300 mg. due to rheumatic fever. (75 mg. 6-hrly). Case 5, a 5-year-old coloured boy, was admitted to the Final Diagnosis.-Rheumatic pancarditis. Children's Hospital of the District of Columbia. He had been well until about 4 weeks before admission when Case 3, a 4-year-old coloured girl, was admitted to the he developed an erythematous rash over the arms and Louisiana State University School of Medicine, having legs, which lasted for 2 days and recurred 2 weeks later complained of foot pain with a swollen ankle 4 days with migratory joint pain, swelling of knee and ankle before admission. joints, and fever. Examination.-On admission her temperature was Examination.-He was an irritable boy with a palpable 104- 8° F., pulse 160/min., blood pressure 86/80. Nothing systolic thrill over the left side of the sternum, was otherwise abnormal. The white blood cell count in the 5th intercostal space within nipple line, grade II was 18,360, and the corrected erythrocyte sedimentation harsh systolic murmur over the entire precordium, but rate 34 mm./lst hour. The electrocardiogram was loudest over the apex, split P2 and A2. There was negative. pitting oedema of both ankles. Course.-She became dyspnoeic and developed gallop Laboratory Tests.-Negative, except for anaemia rhythm, and was given digitalin and oxygen. She died 8-6 g./100 ml., and antistreptolysin-O titre 250 Todd 18 days after admission. units.

Autopsy.-The heart weighed 110 g. (expected 73 g.) Chest x ray revealed increased pulmonary vascularitycopyright. and was dilated; no vegetations were seen on the valves. and an enlarged cardiac silhouette; the liver appeared The lungs weighed 450 g. together (expected 175 g.) and enlarged. were diffusely consolidated; on microscopic section they Electrocardiogram tracings were interpreted as showing showed a severe interstitial pneumonia. AV block and left ventricular hypertrophy. Final Diagnosis.-Rheumatic pancarditis. Clinical Impression. Rheumatic fever and carditis; congestive heart failure; broncho-pneumonia. Case 4, a 10-year-old white boy, was admitted to the with Course.-Despite treatment penicillin, salicylates, http://ard.bmj.com/ New York University Medical Centre. He had been steroids, and digitalin as well as thiomerin and Diamox, well up to 7 weeks before admission when he developed his condition failed to improve: intercurrent broncho- fever 102° F., and had been treated first with sulphon- pneumonia developed and he died on the 28th day in amides and then with penicillin to which he developed hospital. a marked reaction. A murmur was noted on the 10th Final Diagnosis.-Rheumatic fever and pancarditis; day of illness. He continued to have fever, and in the pneumonitis, bilateral, rheumatic; acute passive con- fifth week developed of heart of liver, spleen, kidneys and adrenals; lymph- failure and was given digitalin. 3 days before admission gestion he had become cyanotic and developed a persistent adenitis. on September 28, 2021 by guest. Protected cough. He lost 15 lb. during this illness. Case 6, a 3-year-old Indian boy, was admitted to the Examination.-He was critically ill, dyspnoeic, ortho- Belcourt Indian Hospital, North Dakota, with cough and pnoeic, and cyanotic. The heart sounds were irregular, fever. He had had diarrhoea and vomiting for 2 days, with a harsh systolic murmur at the base, and rales were but this had ceased on the day of admission. He had noted at the base of the lungs. complained of earache on the morning of admission. Laboratory Tests.-All were within normal limits, He had been irritable the previous night and his mother including the white blood count and differential count, had noted painful swelling of the ankles on the morning except for a raised erythrocyte sedimentation rate of admission. (35 mm./lst hour) and a total protein of 5 7 per cent. Past History.-There were no previous illnesses. He Blood culture was negative. had had a fever 3 weeks before admission, when a heart The erythrocyte count was 4,690,000 with Hb 16-5, murmur was noted for the first time, but the throat was and 3,830,000 with Hb 8- 5. not inflamed, and the white blood count and differential An electrocardiogram revealed a right axis deviation counts were not remarkable. He had been treated with and complete auricular-ventricular block. aspirin and chloramphenicol and did not not return for A chest x ray revealed probable broncho-pneumonia follow-up evaluation of the . There was and enlarged heart. no history of allergies or immunizations. Ann Rheum Dis: first published as 10.1136/ard.22.3.127 on 1 May 1963. Downloaded from

ORIGIN OF THE ASCHOFF BODY 141 Examination showed he was W.D. W.N. and very given 0 5 g. streptomycin intramuscularly and was placed irritable, with a temperature of 103-40 F. The right on 2 dr. chloramphenicol 4-hrly. The liver was enlarged TM was injected at its superior margin. The left TM 2 to 3 finger breadths below the right costal margin. was clear. The pharynx was clear. There were muffled Rales were more prominent in the bases of the lungs. rhonchi and rales throughout the lung fields. There There was no swelling of ankles or feet and no joint were mild intercostal retractions. There was a Grade tenderness could be demonstrated on PE. He was III to IV systolic murmur over the precordium, loudest placed on digoxin 0 5 mg. stat and was to receive two at the apex. There was of 180. The more doses of 0-2 mg. 8-hrly. abdomen and extremities showed nothing remarkable At 3.45 p.m. he had alternating periods of stupor and except for puffy swelling around the ankles which seemed increased restlessness with purposeless movement of the to be tender. However, it was very difficult to evaluate hands, arms, and legs, and began to thrash about in bed. this because of his extreme irritability. The pulse rate was 140, and respirations 60/min. Auscul- Laboratory Tests.-White blood count 14,000 (75 tation of the lungs revealed much more prominent rales neutrophils, 2 bands, 18 lymphocytes, 3 monocytes, and rhonchi and he began to foam at the mouth. Sud- 2 basophils). Erythrocyte sedimentation rate 34 mm./ denly his heart stopped, and mouth-to-mouth respiration 1st hour, corrected to 19. Haematocrit 33, Hb 8- 5 g. and cardiac massage were of no avail. X rays showed a rather light patchy infiltrate extending Final Diagnosis.-Acute rheumatic fever, valvulitis, from the hilar regions bilaterally. myocarditis, and pericarditis; severe fatty degeneration Electrocardiogram showed a regular sinus tachycardia of the heart; focal rheumatic pneumonia with hyaline with a * 12 PR interval. The QRS axis was about 70. membranes. Clinical Impression.-Rheumatic fever with possible rheumatic pneumonia. L'origine des nodules d'Aschoff Course.-He was placed on aspirin and procaine RESUME penicillin 600,000 units every 12 hrs. That evening the (1) On 6tudia l'anatomie pathologique de six cas de rectal temperature dropped to 1000 F. and the pulse rate cardite rhumatismale fulminante et de trois coeurs to 138. Attempts to hear the heart murmur were non-rhumatismaux comme temoins. (2) On demontre que le nodule d'Aschoff est un canal unsuccessful presumably because of respiratory noises. lymphatique morbide. copyright. However, the child seemed to be more comfortable and (3) La lesion du myocarde et le derangement de sa less irritable. In the early morning the respirations fonction sont secondaires a une lymphangite obliterante. became more rapid (about 50-60/min.) and the pulse rate 150-158. The child was moaning and rubbing his abdomen as if in pain, but there was no apparent dis- El origen de los n6dulos de Aschoff tension or hardness of the abdomen. The urinary output was good. Later in the morning his condition SUMARIO seemed to worsen despite a normal temperature; the (1) Se estudi6 la anatomia patol6gica de seis casos de http://ard.bmj.com/ carditis reumatica fulminante, con tres corazones non- pulse rate continued to be rapid though it was less than reumAticos como testigos. on admission. (2) Se presenta evidencia de que el n6dulo de Aschoff The electrocardiogram showed no essential changes. es un canal linfatico m6rbido. He seemed to be having more respiratory difficulty and (3) La lesi6n del miocardio y el desarreglo de su was placed in the croupette with alevair. He was also funci6n son secundarios a una linfangitis obstructive. on September 28, 2021 by guest. Protected